Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracerebral hemorrhage (ICH) initiates an inflammatory response with secondary growth of hemorrhage and cell death. Matrix metalloproteinase (MMP) gelatinolytic activity is increased in ICH, and synthetic inhibitors to MMPs reduce edema and hemorrhage size. Recently, we found that tissue inhibitor of metalloproteinase-3 (TIMP-3) is elevated after ischemia and colocalizes with TUNEL (terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end-labeled)-labeled cells. Tissue inhibitor of metalloproteinase-3 promotes neuronal apoptosis in vitro by blocking the shedding of the tumor necrosis factor (TNF) superfamily of death receptors/ligands by stromelysin-1 (MMP-3). However, the effect of TIMP-3 and synthetic MMP inhibitors on cell death in ICH is unclear. Therefore, we used the collagenase-induced intracerebral hemorrhage (CIH) model in Timp-3 knockout and C57Bl/6 wild-type mice to study MMP expression, hemorrhage volume, and cell death. Real-time PCR showed an increase in Mmp-3 mRNA in CIH, but similar Mmp-2 and -9 mRNA expression levels in CIH and saline-injected mice. Protein levels of pro and cleaved MMP-3 were increased in CIH, and zymographic gelatinolytic activity of MMP-9 was elevated after CIH at 72 h, suggesting an exogenous source. Apoptosis was shown by increased caspase-3 levels at 2 and 72 h, and active caspase-8 by 2 and 24 h. The Timp-3 null mouse and wild types had similar hemorrhage sizes and TUNEL-labeled cells. Unexpectedly, the broad-spectrum MMP inhibitor BB-94 increased hemorrhage size and TUNEL-labeled cells. Our results fail to implicate TIMP-3 in apoptosis in CIH, but show that BB-94 increased apoptosis in CIH, possibly by blocking shedding of TNF death receptors and/or their ligands.
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PMID:Matrix metalloproteinase inhibition facilitates cell death in intracerebral hemorrhage in mouse. 1797 90

The last 10 years witnessed the publication of many studies on the pathophysiology of thrombotic thrombocytopenic purpura (TTP), a life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and multiorgan failure. The most important finding was the identification of a novel metalloprotease, named ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motives), that is involved in the regulation of the size of von Willebrand factor (VWF), a major modulator of platelet adhesion and aggregation in the microcirculation. Inherited or acquired deficiencies of ADAMTS13 impair VWF cleavage, leading in turn to the disseminated formation of platelet-rich thrombi in the micro-circulation and to symptoms of end-organ ischemia. By measuring ADAMTS13 in plasma, it has been clearly shown that patients with inherited TTP have severe ADAMTS13 deficiency. However, patients with acquired TTP present with clinical and laboratory heterogeneity, and there are unequivocal cases of acquired TTP with measurable plasma levels of ADAMTS13. This heterogeneity poses a challenge for understanding the pathogenesis of TTP and selecting appropriate therapies.
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PMID:TTP and ADAMTS13: When Is Testing Appropriate? 1802 19

Reductions in vascular density occur following acute ischemia-reperfusion (I/R) injury that may predispose the development of chronic kidney disease. The mechanisms mediating vascular loss are not clear but may relate to the lack of effective vascular repair responses. To determine the regulation of the VEGF/VEGFR pathway following I/R injury, male Sprague-Dawley rats were subjected to bilateral renal ischemia (45 min) and allowed to recover for 1, 3, 7, and 35 days. VEGF mRNA expression was repressed by greater than 50% of control values up to 3 days postischemia, while VEGF protein was repressed for up to 7 days postischemia. The renal mRNA expression of receptors was not altered postischemia; however, VEGFR1 (flt-1) protein was transiently reduced in kidney while soluble flt-1 was elevated in plasma at 7 days following injury. Microarray analysis of angiogenesis-related genes identified the enhanced expression of a number of genes, among these was ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motif-1), a secreted VEGF inhibitor. The altered expression of ADAMTS-1 was confirmed using RT-PCR and Western blot analysis; immunofluorescence localized its expression to proximal tubules following I/R injury. Other genes identified using microarray included aminopeptidase N, Smad-1, and Id-3 and their localization was also examined using immunohistochemistry. In summary, the data indicate no clear pattern of anti-angiogenic gene expression following renal I/R injury. However, the studies do suggest an overall inhibition of the VEGF pathway during the early injury and repair phase of renal ischemia that may contribute to an overall reduction in renal microvascular density.
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PMID:Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor. 1827 97

Proteins with a disintegrin and a metalloproteinase domain (ADAMs) are a family of membrane-bound proteinases that bind integrins through their disintegrin domain. In this study, we have found modest expression of ADAM15 in pericytes in normal retina and strong up-regulation of ADAM15 in retinal vascular endothelial cells in ischemic retina. Increased expression of vascular endothelial growth factor (VEGF) in the retina in the absence of ischemia also increased ADAM15 levels, and knockdown of Vegf mRNA in ischemic retina reduced Adam15 mRNA. Mice deficient in ADAM15 showed a significant reduction in ischemia-induced retinal neovascularization, choroidal neovascularization at rupture sites in Bruch's membrane, and VEGF-induced subretinal neovascularization. ADAM15-deficient mice also showed reduced levels of VEGF(164), VEGF receptor 1, and VEGF receptor 2 in ischemic retina. These data suggest that ADAM15 and VEGF participate in an amplification loop; VEGF increases expression of ADAM15, which in turn increases expression of VEGF and its receptors. Perturbation of the loop by elimination of ADAM15 suppresses ocular neovascularization in 3 different model systems, and thus ADAM15 provides a new therapeutic target for diseases complicated by neovascularization.
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PMID:An Adam15 amplification loop promotes vascular endothelial growth factor-induced ocular neovascularization. 1838 16

Regulation of the extracellular matrix by proteases and protease inhibitors is a fundamental biological process for normal growth, development and repair in the CNS. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) are the major extracellular-degrading enzymes. Two other enzyme families, a disintegrin and metalloproteinase (ADAM), and the serine proteases, plasminogen/plasminogen activator (P/PA) system, are also involved in extracellular matrix degradation. Normally, the highly integrated action of these enzyme families remodels all of the components of the matrix and performs essential functions at the cell surface involved in signaling, cell survival, and cell death. During the inflammatory response induced in infection, autoimmune reactions and hypoxia/ischemia, abnormal expression and activation of these proteases lead to breakdown of the extracellular matrix, resulting in the opening of the blood-brain barrier (BBB), preventing normal cell signaling, and eventually leading to cell death. There are several key MMPs and ADAMs that have been implicated in neuroinflammation: gelatinases A and B (MMP-2 and -9), stromelysin-1 (MMP-3), membrane-type MMP (MT1-MMP or MMP-14), and tumor necrosis factor-alpha converting enzyme (TACE). In addition, TIMP-3, which is bound to the cell surface, promotes cell death and impedes angiogenesis. Inhibitors of metalloproteinases are available, but balancing the beneficial and detrimental effects of these agents remains a challenge.
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PMID:Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. 1862 Nov 8

Thrombospondin-2 (TSP2) is an inhibitor of angiogenesis with pro-apoptotic and anti-proliferative effects on endothelial cells. Mice deficient in this matricellular protein display improved recovery from ischemia and accelerated wound healing associated with alterations in angiogenesis and extracellular matrix remodeling. In this study, we probed the function of TSP2 by performing a detailed analysis of dermal wounds and wound-derived fibroblasts. Specifically, we analyzed incisional wounds by tensiometry and found no differences in strength recovery between wild-type and TSP2-null mice. In addition, analysis of full-thickness excisional wounds by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling stain and MIB-5 immunohistochemistry revealed similar numbers of apoptotic and proliferating cells, respectively. In contrast, the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2, and soluble vascular endothelial growth factor were increased in wounds of TSP2-null mice. Evaluation of the ability of TSP2-null wound fibroblasts to contract collagen gels revealed that it was compromised, even though TSP2-null wounds displayed normal myofibroblast content. Therefore, we conclude that the lack of TSP2 leads to aberrant extracellular matrix remodeling, increased neovascularization, and reduced contraction due in part to elevated levels of MMP-2 and MMP-9. These observations provide in vivo supporting evidence for a newly proposed function of TSP2 as a modulator of extracellular matrix remodeling.
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PMID:Enhanced angiogenesis and reduced contraction in thrombospondin-2-null wounds is associated with increased levels of matrix metalloproteinases-2 and -9, and soluble VEGF. 1902 4

Accumulating evidence indicates that cerebral ischemia enhances neurogenesis in the adult brain. The mechanisms responsible for stem-cell development are poorly understood. Recent in vitro studies indicate the involvement of metalloproteinase (MMPs) in the regulation of proliferation and differentiation of neural progenitor cells. To elucidate if MMPs participate in neurogenesis-associated processes after ischemic insult, we aimed to establish spatial and temporal relationships between neural stem-cell development and the activity of MMPs in the adult brain hippocampus. Our results show that post ischemic acceleration in the proliferation of progenitors in the dentate gyrus is accompanied by increased activity of MMPs. On the contrary, in the damaged CA1 pyramidal layer the neurogenesis seems to be rather elusive. Simultaneously, the activity of MMPs fell below the control level. In conclusion, our results show that the activation of MMPs may, at least in part, contribute to ischemia-induced neurogenesis in the dentate gyrus of the adult brain.
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PMID:Neurogenesis in gerbil hippocampus following brain ischemia: focus on the involvement of metalloproteinases. 1932 41

The serious need for expanding the donor population has attracted attention to the use of steatotic donor livers in orthotopic liver transplantation (OLT). However, steatotic livers are highly susceptible to hepatic ischemia-reperfusion injury (IRI). Expression of fibronectin (FN) by endothelial cells is an important feature of hepatic response to injury. We report the effect of a cyclic RGD peptide with high affinity for the alpha5beta1, the FN integrin receptor, in a rat model of steatotic liver cold ischemia, followed by transplantation. RGD peptide therapy ameliorated steatotic IRI and improved the recipient survival rate. It significantly inhibited the recruitment of monocyte/macrophages and neutrophils, and depressed the expression of pro-inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and interferon (IFN)-gamma. Moreover, it resulted in profound inhibition of metalloproteinase-9 (MMP-9) expression, a gelatinase implied in leukocyte migration in damaged livers. Finally, we show that RGD peptide therapy reduced the expression of the 17-kDa active caspase-3 and the number of apoptotic cells in steatotic OLTs. The observed protection against steatotic liver IRI by the cyclic RGD peptides with high affinity for the alpha5beta1 integrin suggests that this integrin is a potential therapeutic target to allow the successful utilization of marginal steatotic livers in transplantation.
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PMID:Cytoprotective effects of a cyclic RGD peptide in steatotic liver cold ischemia and reperfusion injury. 1968 24

Renal ischemia and reperfusion injury is the major cause of acute renal failure and may also be involved in the development and progression of some forms of chronic kidney disease. The aim of this study was to evaluate whether doxycycline, a member of the tetracycline family of antibiotics, protects kidney tissue or not. 36 Sprague-Dawley rats (200-250 g) were used. The animals were divided into three groups: control, ischemia/reperfusion and ischemia/reperfusion+doxycycline group. Rats were subjected to renal ischemia by clamping the left pedicle for 1 h, and then reperfused for 1 h. The ischemia/reperfusion+doxycycline group were pretreated intraperitoneally with doxycycline suspension (10 mg/kg) 2 h before the induction of ischemia. Our results indicate that malondialdehyde, matrix-metalloproteinase-2, interleukin-2, interleukin-6, interleukin-10, interleukin 1-beta and tumor necrosis factor-alpha levels were significantly higher in the ischemia/reperfusion group than those in the control group. Doxycycline administration significantly decreased these parameters. Tissue inhibitor of metalloproteinases-1 levels also increased after ischemia/reperfusion and decreased with doxycycline pretreatment, but these changes were not significantly different. Glutathione levels significantly decreased after ischemia/reperfusion injury when compared with the control group and doxycycline pretreatment significantly increased glutathione levels when compared with the ischemia/reperfusion group. Apoptotic cells and p53 positive cells were significantly decreased in doxycycline treated group. These results suggest that doxycycline reduces renal oxidative injury and facilitates repair. Doxycycline may play a role in a renoprotective therapeutic regimen.
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PMID:Protective effects of doxycycline in ischemia/reperfusion injury on kidney. 1988 97

Levels of tissue kallikrein (TK) are significantly lower in the urine of patients with kidney failure, and TK expression is specifically diminished in rat kidney after recovery from ischemia-reperfusion injury. In this study, we investigated the functional consequence of blocking endogenous TK activity in a rat model of chronic kidney disease. Inhibition of endogenous TK levels for 10 days by neutralizing TK antibody injection in DOCA-salt rats caused a significant increase in blood urea nitrogen and urinary protein levels, and a decrease in creatinine clearance. Kidney sections from anti-TK antibody-treated rats displayed a marked rise in tubular dilation and protein cast accumulation as well as glomerular sclerosis and size. TK blockade also increased inflammatory cell infiltration, myofibroblast and collagen accumulation, and collagen fraction volume. Elevated renal inflammation and fibrosis by anti-TK antibody were associated with increased expression of tumor necrosis factor-alpha, intercellular adhesion molecule-1, tissue inhibitor of metalloproteinase-2 (TIMP-2), and plasminogen activator inhibitor-1 (PAI-1). Moreover, the detrimental effect of TK blockade resulted in reduced nitric oxide (NO) levels as well as increased serum lipid peroxidation, renal NADH oxidase activity, and superoxide formation. In cultured proximal tubular cells, TK inhibited angiotensin II-induced superoxide production and NADH oxidase activity via NO formation. In addition, TK markedly increased matrix metalloproteinase-2 activity with a parallel reduction of TIMP-2 and PAI-1 synthesis. These findings indicate that endogenous TK has the propensity to preserve kidney structure and function in rats with chronic renal disease by inhibiting oxidative stress and activating matrix degradation pathways.
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PMID:Blockade of endogenous tissue kallikrein aggravates renal injury by enhancing oxidative stress and inhibiting matrix degradation. 2008 75


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